# Mechanism and mitigation of bone marrow microenvironment dysfunction in myelodysplastic syndrome.

> **NIH NIH F30** · UNIVERSITY OF ROCHESTER · 2020 · $50,520

## Abstract

Project Summary:
 The myelodysplastic syndromes (MDS) are the most common myeloid neoplasm in the U.S. They are
hallmarked by bone marrow failure due to ineffective hematopoiesis and production of dysplastic blood cells,
resulting in anemia, leukopenia, and/or thrombocytopenia and a high risk of transformation to acute leukemia.
Overall survival is poor as the current standard of care is inadequate, relying largely on symptomatic
management of cytopenias and limited drugs with low response rates and durability. As MDS predominately
affects older adults, disease prevalence will likely increase with the growing aged population, underscoring the
crucial need now to identify new therapeutic targets in MDS. We and others have demonstrated that alterations
of the bone marrow microenvironment (BMME) in MDS contribute to hematopoietic failure and disease
progression. The BMME normally regulates hematopoietic stem cells to ensure life-long production of blood
cells while preventing neoplastic disease. Although in vitro evidence suggests that marrow stromal cells are
dysfunctional in the MDS BMME and have an impaired ability to support hematopoiesis, the mechanism of
BMME dysfunction remains unknown due to the lack of robust in vivo studies on the interactions between MDS
hematopoietic cells and their BMME. In our recent studies of the NUP98-HOXD13 (NHD13) transgenic mouse
model of MDS, transplantation of NHD13 marrow into the BMME of wild-type mice improved hematopoietic
function, indicating that the MDS BMME is impaired in hematopoietic support and that this can be mitigated
via bulk normalization to a healthy BMME. Moreover, NHD13 mice have abnormalities in BMME osteoblastic
lineage cells and their mesenchymal stromal cell precursors, concurrent with decreased hematopoietic
function. We find that these BMME changes are MDS-dependent derangements, in line with prior reports
describing pathological “reprogramming” of the BMME by neoplastic myeloid cells. Thus, we hypothesize that
MDS cell-derived signals induce dysfunction in mesenchymal-osteolineage populations to impair the BMME’s
ability to support normal hematopoietic function. A corollary to this is that hematopoietic failure in MDS can be
mitigated by blocking interactions of MDS-cell initiated signals with BMME cells. The specific MDS-initiated
signals and the BMME population they interact with are currently unknown. To test our hypothesis, we will
define MDS-induced changes in BMME mesenchymal-osteolineage cells in vivo using the NHD13 model. We
will also identify MDS-initiated signals that impair the BMME and determine if eliminating these signals can
restore health to the MDS BMME and improve hematopoietic function in MDS. These studies will clarify the
mechanism of BMME dysfunction in MDS and its role in hematopoietic failure to potentially identify therapeutic
targets in the MDS BMME to recover hematopoietic function in patients with MDS.

## Key facts

- **NIH application ID:** 9900775
- **Project number:** 5F30DK113727-04
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Allison Jinquan Li
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900775

## Citation

> US National Institutes of Health, RePORTER application 9900775, Mechanism and mitigation of bone marrow microenvironment dysfunction in myelodysplastic syndrome. (5F30DK113727-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9900775. Licensed CC0.

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